Porphyrin derivatives their use in photodynamic therapy and...

Details Porphyrin derivatives their use in photodynamic therapy and... Porphyrin derivatives their use in photodynamic therapy and...

2001-04-30

2003-10-07

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Magnetic imaging agent

C424S009610, C514S185000, C514S410000, C540S145000

Reexamination Certificate

active

06630128

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds, compositions, apparatus and methods for treating a medical condition for which a photodynamic compound is indicated, particularly in the curative or prophylactic treatment of medical conditions such as atherosclerosis, cataracts, restenosis, secondary cataracts, endometrial ablation, bladder cancer, other cancers and proliferative diseases, inflammation and infection.
Photodynamic therapy is a method of treating a diseased tissue of a patient. Typically, the surgical procedure involves administering a photodynamic agent to a patient, such as via an intravenous injection, and then irradiating the target diseased tissue with a separate light source. The photodynamic agent following irradiation with light emits reactive oxygen species, such as singlet oxygen, which disrupt the surrounding cellular tissue.
A problem with prior art methods is that many of the photodynamic agents are relatively insoluble in physiologically acceptable media and they also tend to form aggregates in solution. Such adverse physicochemical properties necessitate complex formulations in order to provide useful materials for medical use. Moreover, as the formulations are typically administered by intravenous injection it is difficult to target the diseased tissue specifically.
Chemistry of Heterocyclic Compounds
23, 186-191 (1987) (Zhamkochyan el al.) disclose s various 5,10,15,20-tetra(4′-vinyl and -allyl phenyl)porphyrin derivatives and their Cu(II), Ni(II), CO(II) and Fe(III)Cl complexes.
Chemistry of Heterocyclic Compounds
23, 645-50 (1987) (Syrbu et al.) discloses monohaloalkyloxyphenyl-triphenyl-porphyrins and dimeric porphyrins.
Chemistry of Heterocyclic Compounds
25, 1149-53 (1989) (Syrbu et al.) discloses tetra-(carboxymethylenoxyphenyl)porphines and their ethyl esters.
Chem. Ber
. 129(9), 1073-81 (1996) (Buchler et al.) discloses metalloporphyrin double deckers formed by reaction of 5-(4-hydroxyphenyl)-10,15,20-tris(4-methyl)phenylporphyrin with &agr;,&ohgr;dibromoalkanes and 1,4-bis(3-bromopropyl)-2,5-dimethoxybenzene.
J.A.C.S
. 112(6), 2440-2 (1990) (Manka et al.) discloses a tetraaminooxyphenylporphyrin derivative.
J. Chem. Soc., Perkin Trans. I
no. 10, 2335-9 (1983) (Milgrom et al.) discloses 5,10,15,20-tetrakis(4-substituted phenoxy)porphyrin derivatives and their metal complexes for use as sensitisers for microheterogeneous water photooxidation.
J. Org. Chem
. 59(24), 7473-8 (1994) (Schneider et al.) discloses 5,10,15,20-tetrakis(4-substituted phenoxy)porphyrin derivatives and their Cu and Zn complexes for potential use as antiviral/antitumour agents.
J. Org. Chem
. 52(5), 827-36 (1987) (Lindsey et al) discloses the preparation of tetraphenylporphyrins.
Tet. Letts
. 38(40), 7125 (1997) (Mehta et al.) discloses an anthraquinone porphyrin derivative for photodynamic therapy.
Tet Letts
. 36(10), 1665-6 (1995) (Latouche et al.) discloses 5,10,15,20-tetrakis(4-(carboxymethylene)phenoxy)porphyrin derivatives and copper complexes in “proteic medium”.
J. Chem. Soc., Perkin Trans. I
no 22, 2667-9 (1993) (Mehta et al.) Discolors an acridone porphyrin derivative for photodynamic therapy.
Tet. Letts
. 35(24), 4201-4 (1994) (Mehta et al.) discloses a porphyrin derivative linked to the anti-cancer drug chiorambucil for photodynamic therapy.
J. Heterocyclic Chem
. 15(2), 203-8 (1978) (Little et al.) discloses covalently linked porphyrin dimers which may include a metal, such as V(IV) or Cu(II).
U.S. Pat. No. 5,594,136 relates to texaphyrins supported on a matrix. The matrix-supported texaphyrins may be used in the separation of neutral and anionic species, in applications concerning phosphate ester hydrolysis, magnetic resonance imaging and photodynamic therapy.
U.S. Pat. No. 5,284,647 relates to meso-tetraphenylporphyrin compounds which have a maximum of two substituents on the phenyl rings.
The present invention therefore seeks to provide improved compounds, compositions, apparatus and methods for treating a medical condition where photodynamic therapy is indicated and open the way for medical conditions which are not currently treated by photodynamic therapy.
DISCLOSURE OF THE INVENTION
According to a first aspect of the invention, there is provided a compound of formula I,
wherein
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, and R
9
independently represent H, lower alkyl, lower alkenyl and lower alkynyl, the latter three of which are optionally substituted or terminated by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
10
, C(O)R
11
, C(O)OR
12
, C(O)NR
13
R
14
and NR
15
R
16;
M represents a metallic element or a metalloid element;
X represents SH, S—]
2
, OH, NHR
15
, CO
2
H, Cl, Br, I, NCO, NCS, CN, C≡CH, CH═CH
2
, MgCl, ZnCl, Li, Si(OR
17
)
3
, SiR
18
(OR
17
)
2
, SiR
18
R
19
(OR
17
), Sihalo
3
, Sihalo
2
R
17
, SihaloR
17
R
18
, silyl, NO
2
, CHO C(O)]
2
O, C(O)halo, C(O)OR
20
, OC(O)halo, C(O)N
3
, thiocyano, or halobenzyl;
Each Y
1
, Y
2
and Y
3
is independently absent or represents O;
Z is absent or represents lower alkylene;
R
10
, R
11
, R
12
, R
13
, R
14
, and R
16
independently represent H or lower alkyl;
R
15
represents H, lower alkyl, aryl or lower alkylaryl;
R
17
, R
18
and R
19
independently represent H, lower alkyl, aryl or lower alkylaryl;
R
20
represents H, lower alkyl, lower alkenyl or C(O)R
21
where R
21
represents an activating group for reaction to form an amide bond such as N-hydroxysuccinimide, N-hydroxybenzotriazole, or pentafluorophenyl ester; and
A-B and C-D independently represent CH═CH or C
2
—CH
2
;
which compounds or a pharmaceutically acceptable derivative thereof are referred to together hereinafter as “the compounds of the invention”.
The term lower alkyl is intended to include linear or branched, cyclic or acyclic, C
1
-C
20
alkyl which may be interrupted by oxygen (preferably no more than five oxygen atoms are present in each alkyl chain). Lower alkyl groups which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
22
and R
23
may represent include C
1
-C
18
alkyl, C
1
-C
17
alkyl, C
1
-C
16
alkyl, C
1
-C
15
alkyl, C
2
-C
15
alkyl, C
3
-C
15
alkyl, C
4
-C
15
alkyl, C
5
-C
15
alkyl, C
6
-C
15
alkyl, C
7
-C
15
alkyl, C
8
-C
15
alkyl, C
8
-C
14
alkyl, C
8
-C
12
alkyl and C
8
-C
10
alkyl. Preferred lower alkyl groups which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
20
and R
23
may represent include C
6
, C
7
, C
8
, C
9
, C
10
, C
11
, C
12
, C
13
, C
14
, C
15
and C
16
alkyl. Preferred lower alkyl groups which, R
17
, R
18
and R
19
may represent include C
1
-C
3
alkyl, especially methyl or ethyl.
The terms lower alkenyl and lower alkynyl are intended to include linear or branched, cyclic or acyclic, C
2
-C
20
alkenyl and C
2
-C
20
alkynyl, respectively, each of which may be interrupted by oxygen (preferably no more than five oxygen atoms are present in each alkenyl or alkynyl chain). The term lower alkenyl also includes both the cis and trans geometric isomers. Lower alkenyl groups which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
20
and R
23
may represent include C
2
-C
18
alkenyl, C
2
-C
17
alkenyl, C
2
-C
16
alkenyl, C
2
-C
15
alkenyl, C
3
-C
15
alkenyl, C
4
-C
15
alkenyl, C
5
-C
15
alkenyl, C
6
-C
15
alkenyl, C
7
-C
15
alkenyl, C
8
-C
15
alkenyl, C
8
-C
13
alkenyl and C
8
-C
12
alkenyl, C
8
-C
10
alkenyl. Preferred lower alkenyl groups which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
20
, and R
23
may represent include C
6
, C
7
, C
8
, C
9
, C
10
, C
11
, C
12
, C
13
and C
14
alkenyl, especially C
10
alkenyl.
Lower alkynyl groups which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
20
and R
23
may represent include C
2
-C
18
alkynyl, C
2
-C
17
alkynyl, C
2
-C
16
alkynyl, C
2
-C
15
alkynyl, C
2
-C
14
alkynyl, C
3
-C
15
alkynyl, C
4
-C
15
alkynyl, C
5
-C
15
alkynyl, C
6
-C
15
alkynyl, C
7
-

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